Other entities represented in this entry:
DO: 14711;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xp11.4 | FG syndrome 4 | 300422 | X-linked recessive | 3 | CASK | 300172 |
| Xp11.4 | Intellectual developmental disorder, with or without nystagmus | 300422 | X-linked recessive | 3 | CASK | 300172 |
A number sign (#) is used with this entry because FG syndrome-4 (FGS4) is caused by mutation in the CASK gene (300172) on chromosome Xp11. Intellectual developmental disorder with or without nystagmus is also caused by mutation in the CASK gene.
FGS4 is typically associated with missense or hypomorphic mutations in the CASK gene. See also the more severe disorder MICPCH (300749), an allelic disorder caused by complete loss-of-function mutations in the CASK gene (Tarpey et al., 2009).
FG syndrome-4 (FGS4) is an X-linked recessive intellectual developmental disorder characterized by congenital hypotonia, constipation, behavioral disturbances, and dysmorphic features (summary by Piluso et al., 2003).
For a general phenotypic description and a discussion of genetic heterogeneity of FG syndrome, see FGS1 (305450).
The name 'FG' derives from the first description of the disorder (FGS1; 305450) by Opitz and Kaveggia (1974), who named it 'FG syndrome' according to the Opitz system of using initials of patients' surnames.
Piluso et al. (2003) identified and clinically characterized an Italian family with FG syndrome, including 31 members with 3 affected males in 2 generations and 2 obligate carriers. At the age of 2 years, the propositus showed marked mental retardation with hyperactive behavior and occasional aggressive outbursts. Relative macrocephaly with prominent forehead and frontal upsweep of hair, hypertelorism, saddled root of the nose with a long philtrum and half-open mouth, micrognathia, congenital hypotonia with joint hyperlaxity, and severe constipation were observed. The mother had mild mental retardation with hypertelorism and long nasal philtrum. She suffered from absence attacks. A 34-year-old maternal uncle of the propositus had been institutionalized since the age of 2 years because of profound mental retardation and aggressive behavior. He also had prominent forehead, hypertelorism, and broad long philtrum. Hypotonia was present in infancy. He had a record of severe constipation and recurrent seizures. EEG was abnormal. His 16-year-old brother likewise showed mental retardation with hyperactive behavior, short stature, and similar facial appearance. Bilateral sensorineural deafness was present. He also suffered from severe constipation.
In 4 families with X-linked mental retardation, Tarpey et al. (2009) identified mutations in the CASK gene. In 2 of the families, nystagmus segregated with mental retardation. Mental retardation was mild to moderate. Hackett et al. (2010) provided clinical details on the families reported by Tarpey et al. (2009), as well on as 2 additional families with the disorder. The phenotype was variable, ranging from nonsyndromic mental retardation to severe MR with microcephaly, brain malformations, and facial dysmorphism. About half of mutation carriers had nystagmus, and some had reduced visual acuity and/or strabismus. Other less common neurologic features included tremor (21%), unsteady gait (16%), and seizures (21%). Only 1 of 3 patients with brain imaging had cerebellar hypoplasia and pachygyria. Affected individuals in 2 families had variable dysmorphic features, including flat midface, open mouth, flat nasal bridge, upslanting palpebral fissures, and short neck. Two female carriers were more mildly affected, but most were phenotypically normal.
Dunn et al. (2017) described a 6.5-year-old boy with nystagmus and FG syndrome-4. The patient presented with delayed development, congenital nystagmus, abnormal balance, and severe feeding difficulties. He was born by repeat Cesarean section at 37.5 weeks, following a pregnancy complicated by preeclampsia. Feeding problems began at 4 weeks of age, initially attributed to milk protein allergy. A gastrostomy tube was placed at 11 months but feeding issues persisted. Postprandial antral hypomobility and gastroesophageal reflux was diagnosed. Facial features included a high and broad forehead, a right cowlick, nystagmus, and broad nose with flat nasal bridge. Language skills and IQ are within normal range; however, visual-motor and motor development, behavior, and working memory were impaired. At 6.5 years, he was still dependent on foods through his G-tube 3 times per day.
Seto et al. (2017) reported a 5-year-old Japanese boy with impaired intellectual development, autism spectrum disorder (ASD), and microcephaly. At age 26 months, a behavioral assessment demonstrated poor verbal communication, impaired social communication, and limited stereotypical interests and behavior. At age 5 years, his physical exam was notable for an occipitofrontal circumference (OFC) of 47 cm (below the 3rd percentile). A brain MRI was normal. The Kyoto Scale of Psychological Development (KSPD) demonstrated an IQ of 61, indicating mild developmental delay. The boy's 3-year-old sister was diagnosed with mild motor developmental delay and ASD. Her KSPD indicated an IQ of 84 (normal).
Piluso et al. (2003) excluded linkage to the known FGS loci in the Italian family with FG syndrome that they reported. An extensive study of the whole X chromosome yielded a maximum lod score of 2.66 (recombination fraction of 0) for markers between DXS8113 and sWXD805. This novel locus for FG syndrome, designated FGS4, corresponds to a region of approximately 4.6 Mb on chromosome Xp11.4-p11.3.
FG Syndrome 4
In affected members of the Italian family with FG syndrome originally reported by Piluso et al. (2003), Piluso et al. (2009) identified a missense mutation in the CASK gene (300172.0003), resulting in exon skipping due to improper recognition of an exonic splicing enhancer (ESE) motif. The mutation segregated fully with the phenotype and was not found in 1,000 ethnically matched control X chromosomes.
In a boy with FG syndrome-4 and nystagmus, Dunn et al. (2017) identified a homozygous splice mutation in the CASK gene (300172.0014). Sanger sequencing in the parents demonstrated that this mutation was de novo.
Intellectual Developmental Disorder with or without Nystagmus
Tarpey et al. (2009) found 4 missense mutations in the CASK gene (300172.0004-300172.0007) that segregated with X-linked intellectual developmental disorder in 4 independent families. In 2 of these families, the mental retardation segregated with nystagmus. Mental retardation was mild to moderate. Tarpey et al. (2009) considered their results and the results of Najm et al. (2008) consistent with the likelihood of missense variants in CASK being less deleterious than truncating variants (see 300749).
In 2 additional families with X-linked intellectual developmental disorder and nystagmus, Hackett et al. (2010) identified 2 different mutations in the CASK gene (300172.0008 and 300172.0009, respectively). In conjunction with the report of Tarpey et al. (2009), CASK mutations were found in 1.5% of individuals with XLMR who were screened. Families with mutations in the C-terminal part of the gene had nystagmus, suggesting a possible genotype/phenotype correlation.
By next-generation sequencing in a 5-year-old boy with impaired intellectual development, autism spectrum disorder, and microcephaly, who did not have nystagmus, Seto et al. (2017) identified a missense mutation in the CASK gene (S475I; 300172.0015). The mutation was identified in his mother and younger sister. Although the sister did not demonstrate impaired intellectual development, she shared autistic symptoms with her brother. The mother showed an almost completely skewed X-chromosome inactivation pattern, whereas the sister demonstrated a paradoxical XCI pattern, with the paternally derived allele predominantly inactivated.
Dunn, P., Prigatano, G. P., Szelinger, S., Roth, J., Siniard, A. L., Claasen, A. M., Richholt, R. F., De Both, M., Corneveaux, J. J., Moskowitz, A. M., Balak, C., Piras, I. S., and 10 others. A de novo splice site mutation in CASK causes FG syndrome-4 and congenital nystagmus. Am. J. Med. Genet. 173A: 611-617, 2017. [PubMed: 28139025] [Full Text: https://doi.org/10.1002/ajmg.a.38069]
Hackett, A., Tarpey, P. S., Licata, A., Cox, J., Whibley, A., Boyle, J., Rogers, C., Grigg, J., Partington, M., Stevenson, R. E., Tolmie, J., Yates, J. R. W., and 10 others. CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes. Europ. J. Hum. Genet. 18: 544-552, 2010. Note: Erratum: Europ. J. Hum. Genet. 18: 552 only, 2010. [PubMed: 20029458] [Full Text: https://doi.org/10.1038/ejhg.2009.220]
Najm, J., Horn, D., Wimplinger, I., Golden, J. A., Chizhikov, V. V., Sudi, J., Christian, S. L., Ullmann, R., Kuechler, A., Haas, C. A., Flubacher, A., Charnas, L. R., Uyanik, G., Frank, U., Klopocki, E., Dobyns, W. B., Kutsche, K. Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum. Nature Genet. 40: 1065-1067, 2008. Note: Erratum: Nature Genet. 40: 1384 only, 2008. [PubMed: 19165920] [Full Text: https://doi.org/10.1038/ng.194]
Opitz, J. M., Kaveggia, E. G. The FG syndrome: an X-linked recessive syndrome of multiple congenital anomalies and mental retardation. Z. Kinderheilk. 117: 1-18, 1974. [PubMed: 4365204] [Full Text: https://doi.org/10.1007/BF00439020]
Piluso, G., Carella, M., D'Avanzo, M., Santinelli, R., Carrano, E. M., D'Avanzo, A., D'Adamo, A. P., Gasparini, P., Nigro, V. Genetic heterogeneity of FG syndrome: a fourth locus (FGS4) maps to Xp11.4-p11.3 in an Italian family. Hum. Genet. 112: 124-130, 2003. [PubMed: 12522552] [Full Text: https://doi.org/10.1007/s00439-002-0863-7]
Piluso, G., D'Amico, F., Saccone, V., Bismuto, E., Rotundo, I. L., Di Domenico, M., Aurino, S., Schwartz, C. E., Neri, G., Nigro, V. A missense mutation in CASK causes FG syndrome in an Italian family. Am. J. Hum. Genet. 84: 162-177, 2009. [PubMed: 19200522] [Full Text: https://doi.org/10.1016/j.ajhg.2008.12.018]
Seto, T., Hamazaki, T., Nishigaki, S., Kudo, S., Shintaku, H., Ondo, Y., Shimojima, K., Yamamoto, T. A novel CASK mutation identified in siblings exhibiting developmental disorders with/without microcephaly. Intractable Rare Dis. Res. 6: 177-182, 2017. [PubMed: 28944139] [Full Text: https://doi.org/10.5582/irdr.2017.01031]
Tarpey, P. S., Smith, R., Pleasance, E., Whibley, A., Edkins, S., Hardy, C., O'Meara, S., Latimer, C., Dicks, E., Menzies, A., Stephens, P., Blow, M., and 67 others. A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation. Nature Genet. 41: 535-543, 2009. [PubMed: 19377476] [Full Text: https://doi.org/10.1038/ng.367]